Preclinical Development of ACXT-3102 for the Treatment of Pancreatic Adenocarcinoma (PDAC)

ACXT-3102 治疗胰腺癌 (PDAC) 的临床前开发

• 批准号: 10435565
• 负责人: WILLIAM G HAWKINS
• 金额: $ 101.92万
• 依托单位: ACCURONIX THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-23 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10435565
• 关键词: Anemia; Antineoplastic Agents; Biological Availability; Body Weight; Cancer Cell Growth; Cancer Etiology; Cancer Model; Cancer Patient; Canis familiaris; Cardiac; Cardiovascular system; Cell Death; Cells; Cessation of life; Chemicals; Clinical; Clinical Trials; Cystine; Data; Development; Disease; Dose; Dose-Limiting; Drug Delivery Systems; Drug Kinetics; Drug Stability; Drug Targeting; Enzymes; Fatigue; Formulation; Glutamates; Goals; Grant; Half-Life; Human; In Vitro; Incubated; Intravenous; Investigational Drugs; Life; Life Expectancy; Ligands; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Mesylates; Metabolic; Metabolism; Microsomes; Modeling; Mus; No-Observed-Adverse-Effect Level; Oral; Oral Administration; Oxidative Stress; Paclitaxel; Pancreas; Pancreatic Adenocarcinoma; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacology Study; Phase; Phase I Clinical Trials; Plasma; Play; Practice Guidelines; Quality of life; Rattus; Regimen; Research; Role; Safety; Schedule; Series; Site; Small Business Technology Transfer Research; Sodium Chloride; Solid; Solubility; Survival Rate; Temperature; Testing; Therapeutic; Therapeutic Index; Time; Toxic effect; Toxicology; Treatment Efficacy; Tumor Volume; Universities; Ventricular; Washington; Work; antiporter; aqueous; base; cancer cell; cancer type; chemical stability; commercial application; cytotoxicity; design; drug synthesis; effective therapy; erastin; first-in-human; gemcitabine; good laboratory practice; improved; in vitro Assay; in vivo; malic enzyme; medical schools; molecular marker; mouse model; nerve damage; novel; overexpression; oxaliplatin; pancreatic cancer cells; pancreatic cancer model; pancreatic cancer patients; pharmacokinetics and pharmacodynamics; physical property; pre-clinical; preclinical development; preclinical study; prevent; programs; side effect; sigma-2 receptor; small molecule; standard of care; tumor; tumor growth; tumor metabolism; uptake

Project Summary/Abstract Pancreatic cancer is a devastating disease with a very low (8%) 5-year survival rate. Therapeutic options are limited in efficacy and many have substantial toxicity. Targeted drug delivery may improve the therapeutic index of cancer drugs by enhancing drug localization to the cancer cell while minimizing off-target side effects. Sigma-2 receptors (S2R) are highly expressed in pancreatic and other cancers compared to healthy cells. Accuronix Therapeutics is developing ACXT-3102, a molecule with therapeutic potential licensed from Washington University School of Medicine in St. Louis (WUSM). ACXT-3102 is comprised of a S2 ligand covalently bound to the ferroptosis-inducing molecule dm-erastin. Preliminary data show that ACXT-3102 increased the cytotoxicity against pancreatic tumor cells in vitro by 35-fold compared to dm-erastin alone. ACXT-3102 has tremendous potential as a novel treatment option for pancreatic and perhaps several other types of cancer. Drug optimization strategies were conducted in a Phase I STTR which resulted in a better yield during drug synthesis, identification of a mesylate salt with high aqueous solubility and improved physical properties suitable for oral drug administration, demonstration of good oral efficacy and discovery that tumors lacking malic enzyme 1 (ME1) are even more sensitive to ACXT-3102. For this Phase II STTR program, Accuronix Therapeutics will continue to work with our research colleagues from WUSM to prepare ACXT-3102 for Investigational New Drug (IND) submission and eventually testing the compound in pancreatic cancer patients. We will conduct a series of preclinical studies to optimize the dosing regimen in murine pancreatic cancer models – understanding if once, twice or three times per day drug administration improves plasma exposure and anti-tumor efficacy while maintaining safety, i.e., avoiding dose- limiting side effects. Studies will also explore if efficacy of our drug can be further improved when given in combination with gemcitabine, a current standard-of-care for pancreatic cancer. Chemical and metabolic stability of ACXT-3102 will be established using in vitro assays to guide storage conditions of the drug and understand which preclinical species best represents metabolism in humans. To obtain data required for the pharmacology and safety sections of the IND package, preclinical studies will be conducted according to Good Laboratory Practice (GLP) guidelines to generate pharmacokinetic (PK) and pharmacodynamic (PD) data for correlating plasma exposures in different species to what is predicted in human. Similarly, formal GLP toxicology studies will be completed using three different doses in rats and dogs to establish the “No Observed Adverse Effect Level” (NOAEL). These data will be used to model exposure levels in humans and establish a safe, first-in-human (FIH) dose for starting our clinical trials in cancer patients. At the conclusion of the Phase II STTR grant, we will have the pharmacology and safety information on ACXT-3102 required for the IND package, and will have established the first dose to be used in patients.

项目摘要/摘要 胰腺癌是一种毁灭性的疾病，其5年生存率非常低（8％）。治疗选择是 效率有限，许多毒性具有重大毒性。有针对性的药物可以改善治疗 癌症药物指数通过增强药物定位到癌细胞，同时最大程度地减少靶向副作用。 与健康细胞相比，Sigma-2受体（S2R）在胰腺和其他癌症中高度表达。 Accoronix Therapeutics正在开发ACXT-3102，这是一种具有从事治疗潜力许可的分子 华盛顿大学医学院（WUSM）。 ACXT-3102已完成S2配体 共价结合到铁凋亡诱导的分子DM-雌蕊。初步数据显示ACXT-3102 与单独的DM-雌蕊相比，在体外对胰腺肿瘤细胞的细胞毒性增加了35倍。 ACXT-3102具有巨大的潜力，作为胰腺以及其他几个的新型治疗选择 癌症类型。药物优化策略是在I阶段进行的，导致了更好的 药物合成期间的产率，鉴定具有高水溶性的丙二酸盐盐并提高了物理 适合口服药物给药的特性，表明良好的口腔效率和发现肿瘤 缺乏苹果酶1（ME1）对ACXT-3102更敏感。 对于此II阶段STTR计划，Accoronix Therapeutics将继续与我们的研究同事合作 从WUSM开始准备ACXT-3102进行研究新药（IND）提交，并最终测试 胰腺癌患者的化合物。我们将进行一系列临床前研究以优化剂量 鼠胰腺癌模型中的方案 - 了解一次，两次或三次药物 给药可提高血浆暴露和抗肿瘤效率，同时保持安全性，即避免剂量 - 限制副作用。研究还将探讨我们药物的有效性是否可以进一步提高 与吉西他滨（Gemcitabine）结合使用，吉西他滨是胰腺癌的当前护理标准。化学和代谢 ACXT-3102的稳定性将使用体外测定法建立，以指导药物的存储条件和 了解哪种临床前物种最能代表人类的新陈代谢。获得所需的数据 IND包装的药理学和安全部分，将根据良好进行临床前研究 实验室实践（GLP）指南生成药代动力学（PK）和药效学（PD）数据 将不同物种的血浆暴露与人类预测的相关。同样，正式GLP 毒理学研究将使用大鼠和狗中的三种不同剂量完成，以建立“未观察到 不良效应水平”（noael）。这些数据将用于建模人类的暴露水平并建立一个 安全，人类（FIH）的安全，用于开始我们在癌症患者中进行临床试验。在阶段结束时 II STTR赠款，我们将拥有IND所需的ACXT-3102的药理学和安全信息 包装，并将确定要在患者中使用的第一个剂量。